1. Field of the Invention
This application relates to anti-inflammatory agents. More specifically, the embodiment relates to compounds of the general formula (1), methods for their preparation, medicaments comprising these compounds, and their use for the treatment of humans and animals.
2. Background and Description of Related Art
According to a report in Morbidity and Mortality Weekly Report (MMWR 2007, 56, 423), arthritis and other rheumatic conditions, e.g., gout, lupus, and fibromyalgia, affect approximately 46 million adults in the United States, resulting in substantial disability and costs of $128 billion annually. The number of U.S. adults with doctor-diagnosed arthritis has been projected to reach nearly 67 million adults by the year 2030, including 25 million adults who are expected to have arthritis-attributable activity limitations. Among 48 states, the median projected increase in doctor-diagnosed arthritis from 2005 to 2030 will be 16%; a total of 14 states are projected to have increases of 30% to 87%.
The report further states that greater use of existing evidence-based interventions and development of new interventions aimed at decreasing pain, improving function, and delaying disability associated with arthritis are needed to reduce the impact of these projected increases, particularly in those states that will be most heavily affected. These statistics, together with recent studies that suggest links between chronic inflammation and many other disorders underscore the importance of anti-inflammatory drugs. Chronic inflammation may be the mediator for many adverse conditions ranging from allergies to serious health impairments such as atherosclerosis, cancer, osteoporosis, Alzheimer's disease and immune disorders such as myopathies, often in conjunction with others, for example systemic sclerosis, and include dermatomyositis, polymyositis, and inclusion body myositis.
There are now over a 100 medications being offered for the treatment of arthritis and related conditions. Over-the-counter and prescription medications are the traditional treatment option for these diseases. With every response, inevitable drug side effects and adverse reactions are common and vary with the individual patient. Patients are often forced to change their drug regiments to minimize specific side effects. This need for change is reflected by such a large drug portfolio and mandates the search for novel drug candidates with minimal side effects. Compounds of formula (1), which are subject to this embodiment, are the result of this effort.
Arachidonic acid metabolism creates a series of prostaglandins and thromboxanes through the cycloxygenase (COX) pathway, and these products, together with leukotrienes from the 5-lipoxygenase (5-LOX) pathways are implicated in many critical physiological events, but also in numerous pathophysiological conditions, especially inflammation and cancer (Simmons, D L, et al., Pharmacol Rev 2004, 56, 387-437).
Cyclooxygenase-2 (COX-2) is an inducible form of prostaglandin-H synthase and mediates prostaglandin synthesis during inflammation. It is also overexpressed in certain tumors and ascribed to carcinogenic events, (J Med Chem 2004, 47, 6195) especially colon carcinogenesis. Similarly, LOX also plays a critical role in tumorigenesis. In one of many citations, it has been emphasized that both 5-LOX and 12-LOX expression is upregulated in human pancreatic cancer cells (Biochem Biophys Res Commun 1999, 261, 218-223).
It is now recognized that controlling aberrant inflammation is a main key in preventing disease. NSAIDs, including naturally occurring substances with anti-inflammatory activity, can achieve this goal by targeting the arachidonic acid metabolizing enzymes directly, or indirectly by preventing or slowing their expression, e.g., through transcription factor NF-κB inhibition (Sethi, G., et al., Exp Biol Med 2008, 55, 629; Van Waes, C., Clin Cancer Res 2007, 15, 1076).
The embodiment relates to a compound of formula (1) with potent activity in the adjuvant-induced arthritis test in rats but weak inhibitions of isolated COX-2 and LOX5, and no discernable activity against isolated COX-1 at the levels tested. This behavior is unusual among common NSAIDs but is consistent with drugs whose prostaglandin synthesis inhibition is the result of inhibition of NF-κB activation (Plummer S M, et al. Oncogene 1999, 18, 6013).
3. Prior Art
The compounds that are subject to this embodiment are novel. The most preferred compounds of this embodiment contain three significant structural features, namely a carboxamide, a pyrimidine and a (4-hydroxy-3,5-di-tert-butyl)phenyl moiety. These structural elements are independently recognized in known medications, but there is no precedent that combines all three in one molecule.